For treatment of diseases due to failure of biological functions, such as diabetes, transplantation of an organ/tissue is an effective therapeutic method. However, in cases of allotransplantation, which causes immune rejection, and in cases of diseases that occur due to autoimmunity such as type I diabetes, patients need to regularly take an immunosuppressant after the transplantation. Since, in general, immunosuppressants nonspecifically suppress immune function, they are known to increase the risk of infections and cancer development, and to cause hypertension, hyperglycemia, and disorders of the liver and kidney as side effects.
On the other hand, a state called immune tolerance is known. Immune tolerance means suppression of action of the immune system against a particular substance. Immune tolerance is a system which allows the immune system to recognize autologous substances as the self, and regulates the immune system such that it does not attack those substances. It is also known that immune tolerance also occurs for nonself such as orally ingested substances such as foods, so that an excessive immune response can be avoided. Some cancers have been shown to be capable of acquiring immune tolerance to avoid attack by the immune system.
Although the mechanism of immune tolerance has not been fully clarified, processes such as central tolerance (disappearance of immune cells reactive with the self) and peripheral tolerance (suppression of, or loss of responsiveness of, reactive immune cells) are known. Examples of cell species which induce peripheral tolerance in the body include regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). It is thought that, if a method for achieving immune tolerance to a transplanted organ/tissue upon transplantation of the organ/tissue can be established, the need to administer an immunosuppressant can be eliminated.
As a device for formation of a capillary-rich site suitable for tissue transplantation, JP 3089299 B discloses a device using a hydrogel (e.g., agarose) as a substrate. This document mentions growth factors (bFGF, aFGF, PDGF, VEGF, TGF-β, and the like) as factors that induce angiogenesis. However, since the device was developed for the purpose of supplying nutrition and oxygen, there is no discussion on immune tolerance in the document.
American Journal of Transplantation 2014, 14: 1533-1542 describes results of a study in which pancreatic islets were transplanted to a space formed under the skin of a rat using the device described in JP 3089299 (using bFGF+heparin as inducers). The document reports that the transplanted tissue could be maintained for a long period without occurrence of rejection irrespective of the fact that the transplantation was allotransplantation and no immunosuppressant was administered. However, its mechanism has not been studied.
JP 10-306027 A discloses a method in which immune tolerance is induced by intraportal or intravenous administration of a tolerogen containing a hematopoietic stem cell, hemopoietic progenitor cell, and/or mature lymphocyte. However, this technique requires cell transplantation, and the cells to be transplanted need to be obtained from bone marrow or the like.
JP 2001-172188 A discloses a method in which a tolerogen containing bone marrow cells is irradiated with radiation, and then administered into bone marrow to induce immune tolerance. However, this technique requires cell transplantation, and the cells to be transplanted need to be obtained from bone marrow or the like.
JP 6-65088 A discloses an immune tolerance inducer comprising, as active ingredients, a cytotoxic cytokine (a physiologically active substance having cytotoxic activity against immune cells, such as lymphotoxin), and an allergic antigen, autoantigen, or transplanted-organ antigen. However, this technique requires administration of the antigen and the cytotoxic factor. Further, since this inducer is effective only for the particular antigen, the factor to which immune tolerance is to be induced needs to be specified.
JP 10-120591 discloses a method for preparing an antigen-specific immune tolerance inducer by binding a peptide composed of 5 to 25 amino acids containing a B-cell epitope and/or T-cell epitope of the B subunit constituting an AB toxin (e.g., cholera toxin or enterotoxin) to the antigen to which immune tolerance is to be induced, via an appropriate spacer. However, this technique requires design/preparation/administration of an agent specific to the antigen. Moreover, since this inducer is effective only for the particular antigen, the factor to which immune tolerance is to be induced needs to be specified.
JP 2004-522725 discloses a method for inducing tolerance to an antigenic substance by administering, to an individual, the antigenic substance or an antigenic portion thereof together with at least one substance which increases the intracellular COX-2 activity and/or the IFN-γ level in the individual. However, this technique requires design/preparation/administration of an agent specific to the antigen. Moreover, since this method is effective only for the particular antigen, the factor to which immune tolerance is to be induced needs to be specified.